Viale Maurizio, Cordazzo Cinzia, Cosimelli Barbara, de Totero Daniela, Castagnola Patrizio, Aiello Cinzia, Severi Elda, Petrillo Giovanni, Cianfriglia Maurizio, Spinelli Domenico
Istituto Nazionale per la Ricerca sul Cancro, S.C. Terapia Immunologica, L.go R. Benzi 10, 16132 Genova, Italy.
J Med Chem. 2009 Jan 22;52(2):259-66. doi: 10.1021/jm801195k.
The reversal of multidrug resistance by 22 molecules [8-aryl-8-hydroxy-5-R'-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones (1a-i) and 8-aryl-8-alkoxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones (2a-m)] related to myocardial-calcium-channel-modulator diltiazem was studied in multidrug resistant A2780/DX3 and their sensitive counterpart A2780 cells. MTT, cytofluorimetry assays, and fluorescence microscopy analyses were used to define activity and accumulation of doxorubicin with or without the diltiazem-like modulators. Of the 22 molecules, 1a, 2f, 2g, and 2m were able to overcome the established criteria for the selection in A2780/DX3 cells (IC(50) reduction > or = 25%), but only 2f, 2g, and 2m caused a significant increase of intracellular accumulation of doxorubicin. In conclusion, experiments lead to the identification of three diltiazem-like molecules able to increase the intracellular accumulation of doxorubicin by inhibiting the MDR1 function, thus potentiating its antiproliferative activity in multidrug resistant A2780/DX3 cells.
研究了与心肌钙通道调节剂地尔硫䓬相关的22种分子[8-芳基-8-羟基-5-R'-8H-[1,4]噻嗪并[3,4-c][1,2,4]恶二唑-3-酮（1a-i）和8-芳基-8-烷氧基-5-甲基-8H-[1,4]噻嗪并[3,4-c][1,2,4]恶二唑-3-酮（2a-m）]对多药耐药A2780/DX3细胞及其敏感对照A2780细胞多药耐药性的逆转作用。采用MTT法、细胞荧光分析和荧光显微镜分析来确定阿霉素在有无地尔硫䓬样调节剂存在时的活性和蓄积情况。在这22种分子中，1a、2f、2g和2m能够满足A2780/DX3细胞筛选的既定标准（半数抑制浓度（IC(50)）降低≥25%），但只有2f、2g和2m能显著增加阿霉素在细胞内的蓄积。总之，实验鉴定出三种地尔硫䓬样分子，它们能够通过抑制多药耐药蛋白1（MDR1）功能增加阿霉素在细胞内的蓄积，从而增强其在多药耐药A2780/DX3细胞中的抗增殖活性。
